The study of biochemical mechanisms that regulate the use of substrates by the developing brain and individual types of brain cells has been the major focus of this laboratory for the past 19 years. Metabolic trafficking of key compounds (including lactate, alanine and malate) between astrocytes and synaptic terminals and/or neurons has a crucial role in the regulation of brain energy metabolism and neurotransmitter biosynthesis due to the compartmentation of enzymes in brain. Recent studies from our group and others provide evidence of multiple compartments of energy metabolism (or TCA cycle activity) in both astrocytes and synaptic terminals, and evidence that lactate and alanine are major components in the trafficking between astrocytes and synaptic terminals in brain. During the next funding cycle we will determine the mechanisms regulating the synthesis and release of lactate and alanine by astrocytes and the regulation of the uptake of these compounds by synaptic terminals and neurons. Since our studies have also shown different lactate transport systems in synaptic terminals as compared to astrocytes, we will further characterize these systems with respect to their response to effectors, especially since this transport is markedly attenuated by phenylpyruvate and alpha-ketoisocaproate which accumulate in cases of PKU and Maple Syrup Urine Disease, respectively. Other studies will focus on the role of malic enzyme since this enzyme may have a key role in both astrocytes and synaptic terminals in providing pyruvate to maintain TCA cycle activity when glucose is low. Malic enzyme may also have a role in production of lactate by astrocytes for trafficking to neurons. These studies will provide crucial information about the synthesis and trafficking of lactate, alanine and malate between astrocytes and neurons and/or synaptic terminals in brain. An imbalance in the production, transport or utilization of any of the metabolites being studies could lead directly to a derangement in the development of the nervous system. Furthermore, information about the regulation of lactate synthesis and utilization should lead to new therapeutic strategies in preventing the lactic acidosis associated with several forms of mental retardation.